Over the past 20 years, the P.I. has performed substantial work in the development of engineered systems for the regeneration of musculoskeletal tissues. Systems inspired by his work in the area of bone and soft tissue have now been implanted in man. Now I will use the collective expertise and insight I have obtained to test a bold, new hypothesis that complex tissues and joints can be created and similarly find their way to clinical use in man. For this I will use principles of Regenerative Engineering, concepts recently published in Science, Translational Medicine that refer to the use of new advances in materials science, stem cell science and the understanding of cues from developmental biology in heuristic approaches toward complex tissue regeneration. I will explore integrating the individual component tissues developed via the regenerative engineering approach using expertise in developing matrix and cell-matrix constructs for engineering tissues. As the next step we will develop what I term integrated graft systems (IGS) such as osteochondral, osteoligamentous, muscle/tendon and vascularized tissues. Subsequent steps will examine the integration of peripheral nerve into the tissue systems and to develop additional component tissues. Cues are important. I will use experience in drug delivery and investigate the use of biological effector molecules such as the bone morphogenetic proteins as cues for differentiation. We have recently described a group of molecules we term inducerons-small molecule inducers of differentiation that may be particularly suited for musculoskeletal regeneration. Working with our collaborator, we will utilize cues from developmental biology, particularly limb regeneration as an important part of our work. Finally, we have gained substantial expertise in electrical/biomechanical cues for tissue regeneration. I believe we can utilize these cues for the generation of new functional joint tissues as well as integrate